抄録

Histamine H<SUB>2</SUB>-receptor antagonistic properties of the anti-ulcer agent T-593, (±)-(<I>E</I>)-1-[2hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2[[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-2-(methylsulfonyl)guanidine, were investigated on [<SUP>14</SUP>C]aminopyrine accumulation in isolated canine gastric mucosal cells and compared with those of ranitidine and famotidine. The potency of T-593-inhibition of [<SUP>14</SUP>C]aminopyrine accumulation stimulated by 10<SUP>-4</SUP> M histamine, with an IC<SUB>50</SUB> value of 1.85× 10<SUP>-6</SUP> M, was approximately 5 times greater than that of ranitidine, but half that of famotidine. T-593 did not affect [<SUP>14</SUP>C]aminopyrine accumulation stimulated by carbachol or dibutyryl-cAMP. T-593 depressed the maximal response of the histamine concentration-response curve with a dose-related displacement to the right, indicating that the nature of the H<SUB>2</SUB>-receptor antagonism of T-593 was insurmountable and included noncompetitive inhibition. The inhibitory efficacy of T-593 was time-dependent and was retained after the cells were washed. The inhibitory potency of (-)-<I>S</I>-T-593, one of the enantiomers, on the [<SUP>14</SUP>C]aminopyrine accumulation stimulated by histamine was approximately twice that of racemic T-593 and it also behaved as an insurmountable H<SUB>2</SUB>-receptor antagonist. However, the potency of (+)-<I>R</I>-T-593 was markedly weak. These results suggest that T-593 has H<SUB>2</SUB>-receptor antagonism that is insurmountable and this agent slowly associates and dissociates with the receptor in isolated canine gastric mucosal cells and that the specific substance causing H<SUB>2</SUB>-receptor antagonism is (-)-<I>S</I>-T-593.